Project Summary Abstract: Our perceptions, behaviors, emotions, memories and intelligence depend on the appropriate synthesis and release of specific neurotransmitters in the brain. Transmitter identity is initially established by genetic programs. It has been thought that transmitters are fixed and invariant throughout life and that the plasticity of the nervous system consists largely of changes in the strength and number of synapses. We have found that experimental perturbations of spontaneous electrical activity and natural changes in sensory stimuli such as ambient light or odors respecify transmitter identity in the spinal cord and brain in the developing nervous system, leading to matching changes in postsynaptic transmitter receptor specification and changes in animal behavior. Strikingly we recently found that transmitter switching and receptor matching also occur in the adult mammalian brain in response to sensory stimuli and can regulate behavior. These discoveries contrast sharply with the general view of transmitter constancy and identify another way that the nervous system adapts to the environment. Here we describe experiments to determine the effect of motor activity in driving transmitter respecification causing changes in behavior. Our proposed research has three specific aims. The 1st aim tests the hypothesis that sustained running activity leads to enhanced acquisition of other motor skills. The 2nd aim tests the hypothesis that sustained running causes the loss of one transmitter that is accompanied by the gain of another transmitter. The 3rd aim tests the hypothesis that preventing the changes in transmitter identity prevents the changes in behavior that are generated by motor activity. The immediate goals of this research are to test specific hypotheses about the effect of motor activity in generating a novel form of plasticity that involves changes in transmitter identity in the adult mammalian brain. We will determine the role of this form of plasticity in the changes in locomotor behavior. The long-term goals are to understand the role of neurotransmitter respecification in procedural learning and memory.